Abstract 13222: Advanced Glycation Endproduct Carboxymethyl-Lysine (CML) and Incident Heart Failure in Older Persons
Background: Advanced glycation endproducts (AGEs) result from chemical modification of proteins under conditions of hyperglycemia or oxidative stress, such as occur in diabetes, chronic kidney disease, and aging. AGE deposition in the extracellular matrix of the heart and vasculature alters its biochemical and biophysical properties, promoting inflammation and atherogenesis, as well as increased cardiac and arterial stiffness. Circulating levels of AGEs have been linked to severity and outcomes in patients with heart failure (HF), but whether higher plasma AGEs increase the incidence of HF has not been previously examined.
Methods: We assessed the relationship between plasma CML, a major AGE in tissue proteins, and occurrence of incident HF in a large cohort of older U.S. adults (Cardiovascular Health Study). CML was measured by ELISA in subjects free of prevalent HF at the 1996-97 exam.
Results: There were 2,906 eligible subjects: age 78±5; 61% women; 17% diabetes; 24% estimated GFR<60 ml/m/1.73 m2; 19% albuminuria. During median follow-up of 9 yrs, 848 HF events occurred. In adjusted cubic spline analysis, the association of CML with HF was positive and linear. After adjustment for potential confounders, including age, sex, race, center, BMI, systolic blood pressure, antihypertensive Rx, diabetes, smoking, alcohol, albumin, and HDL, higher plasma CML was associated with a significantly increased risk of incident HF (HR per SD [225 ng/ml] = 1.14 [95% CI=1.07-1.21]). This relationship persisted after additional adjustment for putative mediators, namely, prevalent coronary heart disease and atrial fibrillation, C-reactive protein, eGFR and urine albumin-creatinine ratio (UACR) (HR=1.12 [1.04-1.20] or additional inclusion of NT-proBNP (HR=1.09 [1.01-1.17]). There was no evidence of interaction by age, sex, race, diabetes, BMI, eGFR or UACR.
Conclusions: In this older cohort, CML was independently associated with increased risk of HF independent of a wide array of potential confounders, as well as putative mediators. These findings provide the first population-based evidence for CML as a risk factor for incident HF in older adults, and suggest that additional testing of AGE-countering therapies could be fruitful in this high-risk population.
- © 2013 by American Heart Association, Inc.